The cutaneous microcirculation plays a central role in a range of skin diseases that are characterized by epidermal hyperproliferation or cutaneous inflammation. Many of these diseases are typified by increased vascular permeability, leading to cutaneous edema and exacerbation of disease. In addition, altered vascular organization and/or neovascularization are associated with psoriasis, skin tumorigenesis, and with tissue remodeling during wound healing. Adhesive interactions between adjacent endothelial cells play a central role in both vascular permeability and in the reorganization and growth of endothelial cells during angiogenesis. VE-cadherin is a cell surface adhesion molecule specific to endothelial cells which plays a crucial role in endothelial growth control, vascular barrier function and in morphogenic events associated with angiogenesis. The extracellular domain of VE-cadherin mediates cell to cell contact, whereas the cytoplasmic tail of VE-cadherin functions as a scaffold for a series of proteins termed catenins, which couple VE-cadherin to actin and vimentin cytoskeletal networks. Although a great deal has been discovered about the molecular interactions that link VE-cadherin to the cytoskeleton, much less is known about how cell surface levels of VE-cadherin are regulated. Preliminary data from our laboratory leads to the hypothesis that the catenins, in addition to linking cadherins to the cytoskeleton, also regulate VE-cadherin presentation at the plasma membrane by regulating VE-cadherin internalization and degradation. Three specific aims are proposed. In the first aim, the ability of the catenin p120 to regulate VE-cadherin internalization and degradation will be tested. In the second aim, the assembly state of the cadherin catenin complex at the plasma membrane and in the endocytic compartment will be defined. In the third aim, specific sequences in the VE-cadherin tail that target the protein for internalization will be ablated using site directed mutagenesis, and the effect of these mutations on endothelial barrier function and branching morphogenesis will be determined. The long-term goal of these studies is to identify the molecular determinants that regulate VE-cadherin cell surface presentation, and thereby expose processes that could be therapeutically targeted to modulate endothelial barrier function and angiogenesis in the context of cutaneous disease.